An oleanolic acid derivative, K73‐03, inhibits pancreatic cancer cells proliferation in vitro and in vivo via blocking EGFR/Akt pathway

Abstract

Oleanolic acid (OA) and its derivatives show potent anticancer function. Pancreatic cancer (PC) is the fourth core motive of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) has been implicated in PC and has been validated as a therapeutic target. Our study demonstrated that K73-03, an OA derivative, was identified as a potent inhibitor of EGFR by using reverse pharmacophore screening and molecular dynamics simulation assays. Moreover, Western blot analysis showed that K73-03 markedly suppressed the levels of phosphorylated-EGFR (p-EGFR) and phosphorylated-Akt (p-Akt). The inhibitory effect of K73-03 on PC cells was assessed in vitro and in vivo. Mechanistically, K73-03 effectively inhibited the cell proliferation of PC cells, and induced apoptosis and autophagy of ASPC-1 cells in a dose-dependent manner. Additionally, pretreatment with chloroquine, an autophagy inhibitor, significantly inhibited K73-03-induced autophagy and enhanced K73-03induced apoptotic cell death. K73-03 also strongly repressed ASPC-1 cells xenograft growth in vivo. Thus, all these findings provided new clues about OA analog K73-03 as an effective anticancer agent targeted EGFR against ASPC-1 cells, it is worth further evaluation in the future.

Biological Activity of Oleanolic Acid Derivatives HIMOXOL and Br-HIMOLID in Breast Cancer Cells Is Mediated by ER and EGFR

“…Similar suggestions were raised by Xie et al, who showed that ERα was the target for OA, and OA upregulated miR-503 expression through ERα in RAW264.7 cells (macrophage-like cells) [ 49 ]. Moreover, the OA analog, K73-03, was used as an effective anticancer agent that acted via targeting EGFR in pancreatic ASPC-1 cancer cells [ 50 ].…”

Pancreatic Cancer Management by Pentacyclic Triterpenes

“…The titled compound caused G2/M-phase arrest and suppressed ASPC-1 cells migration. Immunoblot assay exposed that K73-03 repressed the phosphorylation EGFR and Akt leading to a remarkable in vitro and in vivo anti-PC effect [72].…”

Application and Development of Natural Plant Metabolite Oleanolic Acid in the Nano Era

“…Nuclear factor-κB (NF-κB) signaling pathway Anti-inflammatory, antitumor [65][66][67][68] Nod-like receptor pyrin domain containing 3 (NLRP3) signaling pathway Anti-inflammatory, neuroprotection [69][70][71] Extracellular-signal-regulated kinase (ERK) signaling pathway Liver protection, antitumor [72,73] Protein kinase B/Akt signaling pathway Antitumor, liver protection [72,74,75] Jun N-terminal kinases (JNK) signaling pathway Antitumor [1,75] Orphan receptor γ t signaling pathway Anti-inflammatory, anti-asthma [76] Mitogen-activated protein kinases (MAPK) signaling pathway Anti-inflammatory [77,78] MiR-122/cyclin G1/myocyte enhancer factor 2D (miR-122/CCNG1/MEF2D) signaling pathway Antitumor [79] Cyclic adenosine 3 ,5 -monophosphate/protein kinase A (cAMP/PKA) signaling pathway Lowers blood sugar and blood lipids, protects pancreatic islets [80] Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway Anti-osteoarthritis [81] Endothelial nitric oxide synthase/Akt/nitric oxide (eNOS/Akt/NO) signaling pathway Ameliorates high glucose-induced endothelial dysfunction [82] Signal transducer and activator of transcription 3 (STAT3) and sonic hedgehog (SHH) signaling pathway Inhibits colorectal cancer [83] Mitogen-activated protein kinase kinase (MEK)/ERK/JNK signaling pathway Anticancer [84] Hippo-Yes-associated protein (Hippo-Yap) signaling pathway Anti-stomach cancer [85] Epidermal growth factor (EGFR)/AKT signaling pathway Anti-pancreatic cancer [86] Nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway Liver protection, antidiabetic, anti-inflammatory, maintenance of redox and protein homeostasis [87][88][89] 3.1. Anti-Inflammatory Effect of OA…”